Synthesis of ethers of vitamin a



Patented Aug 14,1945

UNiTED STATES PATENT OFFICE t A I FVlTAIIN A Nicholas A. Mllas, Belmont, Man a'flgnt to ResearchCorporatlmNewYorLN.Y.,aeerporation of New York No Drawing. Application January 8 1, 1!,

Serial No. 51555. 7 g 11 Claims. (Cl. 280-011) An object 01' the present invention is to pro-' vide a new method for the synthesis of ethers or vitamin A. This application is a continuationin-part of my application Serial Number 400,314, tiled September 2, 1941. In said application I,disclosed several methods for the synthesis of ethers of vitamin A based upon the concept of starting with the aldehyde compound CH: CH:

and the ketone compolmd CH: oec-cflrcflro-c n Compoundn in which R stands 'to'r hydrogen or a hydrocarbon g'i'oup. The group I metallo' derivative thereof, the product hydror genated to convert the acetylene bond into an jethylene bondand the two components dehydrated either before or after their combination.

The present application is concerned with the method in which the ca'rbinol of Compound I is dehydrated before being combined with OompoundII.

The principal steps involved in this process,

starting with'Compounds I and II are the following.

Compound I is converted into the co ponding acetylene carbinol compound which is dehydrated and the dehydrated product converted to the corresponding Grignard or metallo derivative (metal of the first group of the periodic system), the latter is thenpreacted with Compound 11 to form Compound V! which is converted to the vitamin A ether by two routes: (1) it is partially and selectively hydrogenated (acetylene-olefin) andthe earbinolsoiormeddehydratedordehydrohalogenated to the vitamin A ether; (2) it is directly dehydrated to the polyen-yne (Compound VII) which is then partially and selec- 5 tively hydrogenated to the vitamin A ether. The

following equaflons illustrate the process.

CH: m

HCECK K--CHJJOHO+NainIII. IEdI H orLi Ocnpcnudli o is F i H=CH -o-czc1s n H; V

Oompcmdm One E =C-C5CH CompoundlV Grignardmgent 85 'colnpoundlvualhlimstelin liquidNHa v V "OH: CH: OKs

CH 01! L% 0'1)! 0 H CH:

Com Vinwhicii Xstandlior the grouporsmetalolthe cgrnpoundvwunpeundll CH; 0 OK:

m i H CH: I E GH=CE =C-CEGJ1OHgCHs0C B H B 11 cm J ocnpoundvl to obtain the pure P undIlI.

CompoundVi dehydration ether of A v In the following specific examples of procedures for carrying out the reactions outlined above, the preparation of the ethyl ether of vitamin A will be used as illustrative and the compounds will be referred to by the numbers used in the above equations with the additional designation ethyl.

Preparation of Command m, t. e. the acetylene carbinol of Compound I 7 Compound I is condensed with sodium or lithiumacetylidesinamixtureoi'anhydrous ether and liquid ammonia at be-' After the reaction assaose PBn in pyridine, and subsequently removing hydrogen bromide'with alcoholic potash.

Preparation of the Gfiynard Compound V) of Compound IV To one mole-equivalent or ethyl magnesium bromide in anhydrous ether add slowly with stirring at and in an atmosphere or N: one mole-equivalent of Compound IV. 1. e. the dehydrated acetylene carblnolor aldehyde Compound I. Allow the mixture to warm up to room temperature and reflux it gently for about 10 hours.

* 5 Reacting Compound V withCompound II ethyl to produce Compound VI ethyl- The reaction mixture or thei'oregoing operation containing Compound V, i. e. the Grignard of the dehydrated acetylene carbinoi ot Compound I'is cooled to 0 C. and one mole-equivalent of Compound II ethyl added in an atmosphere of N: and the mixture refluxed torabout 24 hours.

The mixture is then cooled and poured into a mixture of ammonium sulfate and ice and the is over, the ammonia is removed and the product treated with a dilute solution of tartaricacid, al-

though aqueous solutions of ammonium sulfate,

ammonium chloride or-other organic acids may 'alsobeused. Theresultingcompoimdmis extracted iromthismixture'inanimpure state and-maybepurined'eitherbyhighvacmim diareaction product, Compound VI ethyl, extracted with ether from which it isrecovered and purifled, by removing the unconverted acetylene with alcoholic ammoniacal silver nitrate solution.

Compound VI ethyl may be hydrogenated either chemically or catalytically yielding predominantly the trans or cis isomer respectively of Compound vm which latter is then" dehydrated to the trans or cis isomer respectively of the ether of vitamin A, or Compound VI may be dehydrated to Compound VII which then ,may be reduced either chemically or catalyticallyto yield predominantly the trans or cis isomer respectively oi the ether or vitamin A.

Dehydration of Compound VI-ethyl to Compound VII-ethyL-To 250 cc. of pure toluene was added 0.3 g. of p-toluene sulfonic acid monohydrate. To dehydrate the p-toluene'sulfonic acid, 100 cc. of toluene was distilled carrying the water with it. The solution was then cooled in nitrogen and to it was added 9.5 g. of Compound VI in 250 cc. of toluene and'about 150 cc. of

tillation in an inert atmosphere or by preparing I its phthalic acid ester by reacting the mixture with phthalio anhydride in pyridine solution. The phthalic acid ester issubsequently saponifled acetylene carbinol, Comc mpo nd III may be prepared also by the interaction of the mono-Grignard oi. acetylene (HICECMgX) and the aldehyde of Compotmd I.

Dehydration 0] Compound III to Compound IV Compound III may be dehydrated by distilling under high vacuum with small amounts of naphthalene sulfonic acid, p-toluene sulionic acid or a mixture of these acids with succinic anhydride yielding Compound IV directly.

A preferred method of dehydrating Compound III without appreciabledecomposition is by passing it upwards at low pressures (0.1-1 mm.)

through a tube packed with aluminum phosphate deposited on pumice and maintained at temperatures between 270 and 290 C. The lower boiling polyvinyl acetylene IV is condensed atthe top of the tube and further purified by finetional distillation. However, better yields of Compound IV areobtained by preparing the bromide or chloride of Compound III, iofiexample by reacting it with toluene was distilled innitrogen. The mixture was then cooled to room temperature and shaken with 150 cc. of methanol containing 3 g. of

potassium hydroxide. Water was then added to separate the alcohol from the toluene layer, the

latter removed, dried'and the tolueneremoved under reduced pressure. .The residue was further purified first from olefin-free petroleum ether then dissolved in 90% methanol and extracted with petroleum ether and finally i'ractionated successively in 10 interval from 0 to ---78 using anhydrous methanol as solvent.

Conversion of Compound VII-ethyl into vitamin A ethyl ether.-It lswell known that in the partial hydrogenation of an acetylene bond attached to two different groups as in the caseo! compound V11, to give the corresponding oleiln, the latter may be present in-two diflerent isomers cis and trans. The proportion of these two isomers depends upon the methodusedto add the two hy-' drogen atoms to the acetylene bond. For instance. it selective catalytic hydrogenation is em-' ployed the predominant isomer present is cis, whereas it a chemical method (e. g. a metal orits amalgam of the flrstvand second groups of the periodic system alcohol, liquid ammonia or any substance which gives "nascent hydrogen on reacting with the metal, zinc aluminum or their amalgams or certain alloys oi these metal are allowed to react with inorganic or organic bases or organic acids to give "nascen hy scn i used the predominant isomer present is trans. Examples of each of these two methods are given in the following disclosures: I

(1) Catalytic method-To 50 cc. of absolute alcohol was added 0.3398 g. of 10% palladium nydroxide on calcium carbonate and the palladium hydroxide reduced with hydrogen gas into palladium black. To this mixture was then added 1.6505 g. of Compound VII in 25 cc. of absolute alcohol and hydrogen gas was introduced until 127 cc. (N. T. P.) was absorbed. The, reactionwas stopped and the vitamin A ether recovered.

(2) Chemical method-Compound VII (2.031 g.) dissolved in 26 cc. of anhydrous methanol was added to100 cc. of 90% ethanol containing 6 g. of solid potassium hydroxide and to this mixture was added 0.52 g. of zinc dust. Gentle stirring was provided by nitrogen bubbling through the mixture for seventeen hours. The reaction mixture was then diluted with water and extracted with olefin-free petroleum ether, the latter dried, filtered and the petroleum ether removed.

This partial reduction was also accomplished by using an organic acid (acetic acid) in alcoholic solution with zinc dust instead oi alkali.

Conversion of Compound VI-ethyl into -cis- Compound VIII-ethyl (catalytic method) .-To 100 cc. of absolute alcohol was added about 0.6 g.

of 10% palladium hydroxide on calcium carbonate and the palladium hydroxide reduced with hydrogen gas into palladium black. To this mixture was th'en added 3.3 g. of Compound VI-ethyl in '50 cc. of absolute alcohol and hydrogen gas introduced until about 225 cc. (N. T. P.) was absorbed.

5-cis-Compound VIII-ethyl was dehydrated to the 5-cis vitamin A ethyl ether in boiling toluene with small amounts (2% of the weight of Compound VIII-ethyl) of p-toluene'sulfonic acid.

In theconversion of 5-cis-Compound VlII-ethyl into the 5-cis vitamin A ethyl ether, one may use the following procedure: Dissolve 0.2 of a mole of 5-cis Compound VIII-ethyl in about 150 cc. of anhydrous toluene and add to the mixture 30 g. of anhydrous pyridine. 0001 the mixture to between 0 and -5 C. and add with rapid stirring 0.42 of a mole of phosphorus tribromide. Allow the mixture to warm slowly to room temperature and increase the temperature to about 50 C. and keep it there for one to two hours. The mixture will become brown. Cool and add to it 300 cc. of 95% alcohol containing 0.45 of a mole of solid potassium hydroxide. The mixture will h'eat up but do not allow the temperature to exceed the boiling point of the alcohol. Keep it at this temperature with nitrogen passing through the solution for two to three hours, then remove most of the alcohol under reduced pressure. Cool and dilute the mixture with about four volumes of cold deoxygenated water and separate 'the resulting layers. Extract the aqueous layer once or twice with petroleum ether and combine nonaqueous extracts. Extract the non-aqueous solutions with 5% aqueous tartaric acid solution. Finally, dry the non-aqueous solutions, remove the solvents under reduced pressure and subject the residue to a high vacuum at not higher than 60- .80' C. (bath temperature) in order to remove volatile constituents.

Conversion of Compound VI-ethyl into 5- trans-compound VIII-ethyl (chemical method) .--Compound VI-ethyl (3.3 g.) dissolved in about 25 cc. of anhydrous methanol was added to potassium hydroxide and to this mixture 'was added 0.8 g. of zinc dust. Gentle. stirring was provided by nitrogen bubbling through the mixe ture ior about 20 hours. The reaction mixture was then diluted with water and extracted with olefin-free petroleum ether, the latter dried and the petroleum ether removed. The residue was 5-trans Compound VIII-ethyl;

Conversion of S-trans Command VIII-ethyl into 5-trans vitamin A ethyl ether.This conversion was accomplished either by dehydration using p-toluene sulfonic acid in boiling toluene. or by the dehydrobromination method described previously.

Compound IIethyl used in the preparation of the ethyl ether of vitamin A may be prepared as described in my application Serial No. 409,314..

Compound I may be prepared as described in my application Serial No. 353,775, filed August 22. 1940.

For the preparation of the trityl ether of vitamin A one starts with Compound 11 phenyl, that is. Compound II in which the three R's stand for phenyl groups, which may be prepared as described in my application Serial No. 409,314 instead of Compound II ethyl as described above.

Instead of forming the Grignard of Compound IV as described above and reacting it with Compound II to produce Compound VI ethyl, the same result may be obtained by" forming the metallo (metal of the first group of the periodic system) compound of Compound IV and reacting it with Compound II. Thus; an alkali metal such as lithium is dissolved in liquid ammonia and an 1 equivalent quantity of Compound IV is added. To the resulting mixture, at a temperature between and 70 an equivalent amount of Compound 11 is added with rapid stirring. After stirring for 24 hours, the ammonia is removed and the residue treated with a cold aqueous mixture of ammonium sulfate or chloride. The product Compound VI is then extracted with ether and purified as in other cases.

The final product i. e. the vitamin A ether pre- I pared by any of the methods described above may be puriiied either by high vacuum distillation (10- to 10- mm. Hg) or fractional crystallization at low temperature or both.

A preterred method of making the ethers of p-hydroxy butanone-2 is as follows:

Addition of methanol to methyl vinyl ketone. A mixture of 3 g. of red mercuric oxide, 2 cc. of boron tri-iluoride-etherate and 2 cc. of anhydrous methanol was placed in a S-necked flask equipped with a condenser, a droppins funnel and a mercury sealed stirrer. protected with calcium chloride tubes. The mixture was then stirred and heated on a steambath until a grayish white paste was formed. The catalyst was then allowed to cool to room temperature and to it was added 30 g. of anhydrous methanol. To this mixture was then added dropwise, in the course of forty minutes with stirring, a mixture of 128 g. of methyl vinyl ketone and 06 g. of methanol. The mixture was refluxed on the steam-bath for one hour, then allowed to stand at room temperature for 24 hours.

Finally. the mixture was neutralized with solid anhydrous potassium carbonate, filtered, and fractionated. The fraction boiling at to was collected and allowed to stand until the colloidal mercury precipitated and was removed.

100 cc. of 90% ethanol containing 5 g. of solid The crude product was then fractionated and All inlets we're the fraction boiling at 142'-146 (yield, 63 g.) collected and analyzed.

Anal. calcd. for 05111002: C, 58.82: H, 9.8.

hydrogen and hydrocarbon. groups.

2. Product as defined in claim 1 in which each R stands for a phenyl group.

3. Product as defined in claim 1 in which two R's stand for hydrogen and one R stands for a methyl group. I

4. As a new product a compound 01' the formula in which R is a member of the group consisting of hydrogen and hydrocarbon groups.

5. Process for the synthesis of vitamin A ethers which comprises reacting a compound oi'cthe tormula in which R stands for a member of the group consisting or hydrogen and hydrocarbon groups, with a compound of the formula CH: CH:

in which x stands for a member of the group consisting of the Grig'nard group and metals of the first group 01 the periodic system.

8. Process as defined in claim 5 in which] x is a Grignard group. i

7. Process asdefined in claim 5 in whichxis a metal of the first group oi the periodic system.

8. Process as defined in claim 5 in which the product oi the reaction is hydrogenated chemically.

product of the reaction is hydrozenatedcatalytically.

10. Process as defined in claim 5 in which the product of the reaction is dehydrated and then hydrogenated chemically.

11. Process as defined in claim 5 in which the product or the reaction is dehydrated and then a hydrogenated catalyticaliy.

NICHOLAS A. MILAS.

9. Process as defined in claim 5 in which the: 

